PROJECT SUMMARY AND ABSTRACT Background: Cannabis is the most commonly used illicit drug worldwide. The potency of cannabis has increased and so has the use of highly potent synthetic cannabinoids (`Spice'). Furthermore, the ?medical? and recreational use of cannabis is increasingly being legalized across the U.S. Therefore, it is important to understand the consequences of chronic cannabinoid exposure on the brain, including the consequences of these changes on neural function, and importantly if/how these evolve when cannabis use stops. Cannabinoid receptor (CB1R) availability can be measured in vivo using Positron Emission Tomography (PET). Neural oscillations, an index of information processing, are sensitive to the effects of CB1R activation and can be measured using electroencephalography (EEG). Hypotheses: Cannabis dependent subjects (CDs) will show lower CB1R availability at baseline relative to controls. CB1R availability will begin to normalize after 48 hours of abstinence (but not to HC levels) and will return to control levels after 4 weeks of abstinence. CDs will exhibit decreased ?- and ?-band neural oscillations compared to HCs at baseline, which will be most disrupted after 48 hours of abstinence and will return to control levels after 4 weeks of abstinence. Across the 3 time points, measures of ?- and ?-band oscillations will correlate with CB1R availability. Finally, CB1R availability, ?- and ?-band power, and coherence will correlate with performance on the cognitive tasks. Methods: The proposed study will utilize 1) CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) and 2) EEG to evaluate the temporal course of CB1R availability and neural oscillations, respectively, in cannabis-dependent individuals (n=25) at baseline (smoking cannabis as usual), following brief (48 hour) monitored inpatient abstinence (when cannabis withdrawal is most likely to occur), and after prolonged (4 weeks) monitored abstinence. Neurocognitive outcomes (e.g., verbal learning) which are known to be impaired by chronic cannabis exposure will also be assessed in order to relate the receptor and electrophysiological findings to domains germane to ?real world? functioning. A sample of healthy control individuals (n=12) will also be assessed at the same time points. This design will allow both within-subject and between-subject analyses across three time points.Taken together, it is hoped that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on CB1Rs, and will shed new light on the status and function of CB1Rs during active cannabis use, and withdrawal.